This invention relates to the detection of leaks in containers (e.g. ampoules) and more particularly to the optical detection of leaks in ampoules based on the dye bath technique.
The detection of leaks in sealed containers has been a problem for many years. Depending upon the container and its contents leaks could be a hazard to life and property; for example, a leaking canned good could lead to food poisoning. Methods used in detecting leaks are perhaps as varied as the types and kinds of containers available and the materials to be found therein.
The particular container of major interest regarding this invention is the ampoule generally used to contain a pharmaceutical substance. The ampoule is a substantially cylindrical, generally glass container, usually transparent or translucent, having a flat base and a rounded-off top portion of reduced cylindrical dimension sitting atop an even narrower neck portion. Glass ampoules are extensively used in the pharmaceutical and chemical industries for the storage and shipment of solutions of drugs and chemicals, both liquid, gases and solids.
The ampoule is normally filled with the desired substance via the top portion, and therefollowing a glass seal is effected at the tip. The primary location of leaks is, as might be expected, associated to this final seal at the tip of the ampoule.
Even today, such seals are inspected visually by human inspectors inverting, shaking and holding the ampoule up to a strong diffuse backlight. It is, of course, of fundamental importance, considering the nature of the substances under particular consideration here, that the ampoule seal be absolutely complete, or the contents of the ampoule may become contaminated.
It has been discovered that, although the seal appears to be perfect, the filled ampoule may start to leak a minute quantity after only a short time and/or over a more extended period.
Heretofore, detection of such leaks was effected by exposing the ampoule to some substance that was known to react with the ampoule contents and which would leave a visible reaction product. Hopefully, even minute leakages would leave a visible indication and the affected ampoule would be correspondingly removed from the lot.
However, not only must the chosen substance to which the ampoule is to be exposed be able to react with the ampoule contents, the amount of visible reaction product is necessarily limited to being proportional to the amount of contents brought into contact with the reacting substance (i.e. that have leaked out or vice-versa). For very small leaks, sometimes called microleakers, the reaction product is obviously correspondingly very small. such circumstances make the detection of very small leaks difficult especially with the ampoules being visually inspected by humans for the presence of the reactant. Nevertheless, this step constituted an improvement over unaided human inspection.
Another known method of detecting leaks in ampoules may be generally identified as the bubble detection technique. This technique involves compressed air being applied via a (Plexiglass) nozzle arrangement to the top portion of the ampoule. The positive pressure is constantly applied and of known value. The ampoule is oriented upside down in the nozzle with the liquid in the ampoule thus completely filling the top portion. Each ampoule remains under test over a set period of time, generally one minute, and is assumed good if no bubbles are detected in that time. Inspection is normally performed by human beings, although seemingly could instead be performed by some sort of suitably arranged bubble detector.
The bubble detection method, in addition to being limited by the inherent problems associated to human visual detection or by the need for expensive bubble detection arrangements, is also rather restricted in effectness to the exact portion of the ampoule being placed under pressure, and most of the exterior surface of the ampoule thus goes uninspected. Also, such a technique does not lend itself to the high volume industrial environment.
A further existing method involves detection of leaks by establishing a loss of weight. In this method a vacuum is applied to the ampoule and a subsequent weighing performed. Although such a method may be satisfactory under laboratory conditions, the inherent complexity and slowness alone involved in weighing each ampoule separately (and twice), as would be necessary particularly in regard to ampoules containing pharmaceutical substances, and particularly in an on-line industrial environment, would generally rule this technique out as an acceptable alternative.
The search for a better technique for detecting the existence of leaks in ampoules has in recent years centered upon the now U.S. FDA-accepted technique of exposing the ampoules to a dye solution. With an incomplete seal the contents of an ampoule could leak out, and if such an ampoule were placed in a dye solution, a certain amount of the dye should be able to "leak in". Since ampoules generally are filled and sealed at atmospheric pressure the dye diffusion rate into the ampoule could be increased by placing the ampoule and dye bath in a suitable temporarily pressurized (positive pressure) environment. The results for a leaky ampoule will normally be a dye tint within its contents.
More particularly, seal integrity of the ampoules is usually checked at the present time by the complete immersion of each ampoule in a concentrated blue dye solution (e.g. 25.times.10.sup.-6 g/ml of Food Drug and Cosmetic (FD&C) blue #1 triphenylmethane dye), with a vacuum pressure of twenty-eight inches of mercury being established for thirty minutes. Upon release of the vacuum the concentrated dye is drawn into the ampoules through any small leaks in the glass. Subsequent handling of the ampoules mixes the dye and its color is detected visually by the inspectors who then reject those leaky ampoules.
It will be apparent that the dye "flagging" technique also suffers from at least the two factors of: (1) the viewability of the "flag" being proportional to its concentration within the ampoule contents; and (2) the detection of the "flag" remaining in the work task of human inspectors. For example, it has been determined experimentally that for a given commercially available product, 1.08 micrograms of dye per ml of solution was the minimum concentration detectable (zero defects level of detection) by the inspectors using diffuse light panels to backlight the ampoules. This figure is a function of ampoule and compound tubidity and color.
The above-quoted figure, although somewhat impressively small, by no means lays to rest the question of whether smaller leaks with correspondingly smaller dye concentrations can exist, and whether such leaks can be tolerated. It has been found that smaller leaks do exist; and depending upon the substance of interest, especially a pharmaceutical product, it is entirely unlikely that any detectable leakage could be tolerated. For example, ampoules passing such tests as have been described hereinabove have later been demonstrated to have holes, as indicated by the presence of dried material on the outside near the seal. Microscopic examination thereof has shown that the holes can have external diameters of approximately 40 .mu.m, narrowing to about 3 .mu.m typically.
One of the more recent and rigorous leak tests that has been developed to prove the structural integrity and sterility of ampoules involves placing for example a helium atmosphere in the ampoule prior to sealing. Following sealing and sterilization, the ampoule is tested with a mass spectrometric leak detector for the passage of helium. Using a mass spectrometer with a sensitivity limit of say 1.times.10.sup.-10 standard cm.sup.3 of He/s, it is calculated that a hole 0.9 .mu.m in diameter and with a length of 1 mm would be detectable with a leak rate of 3.5.times.10.sup.-8 standard cm.sup.3 /s. (Bacteria cannot pass through holes this small.) This technique could also be applied with nitrogen or air atmospheres.
Although perhaps even more rigorous tests can or have been developed, such techniques are, for industrial purposes, generally far too complex, slow and cumbersome, especially for handling of large volumes of throughput, and involve expensive equipments requiring highly trained personnel.
Several other prominent factors facing a manufacturer of the kinds of products with which this discussion relates contribute to the need for an improved system for inspecting filled ampoules. These include the desire to increase the speed of the inspection process, particularly in a high volume industrial environment, and to remove the troublesome inter- and intra-inspector differences, as well as enable the detection of the presence of lower dye or other "flag" concentrations (e.g. microleakers).